Mesna, also know as Uromitexan.RTM., is the common name for the compound sodium-mercaptoethanesulphonate. The compound mesna is hygroscopic, freely soluble in water, sparingly soluble in methanol and practically insoluble in conventional organic solvents. The compound mesna has been used for the prevention of urinary tract toxicity caused by various anti-tumor drugs, such as Endoxan.RTM. (ifosfamide), Holoxan.RTM. (trofosfamide) and Ixoten.RTM.. When mesna is employed for the foregoing purpose, side effects such as irritations of the veins or hypersensitivity reactions are extremely rare if mesna is used in a single dose of 60 mg mesna/kg body weight. However, if mesna is administered in excess of this dosage, nausea, retching and diarrhea have been observed. Mesna has also been employed in low doses, such as 21.5 mg per kg, as a reliable protection against the urotoxic effects of chemotherapeutic drugs, e.g., oxazaphosphorine derivatives, particularly, cyclophosphamide.
In toxicity tests, the LD 50 values determined for rats and mice after i.v. or i.p. administration are between 1,200 and 2,000 mg/kg; after oral administration in mice, greater than 6,000 mg/kg; and in rats about 4,500 mg/kg. In dogs, death was observed after intravenous doses of 400 mg/kg and above, but not after oral doses of up to 2,000 mg/kg. Accordingly, mesna is indicated to exhibit beneficial effects when used to protect a patient against the ravages of chemotherapy.
There is much literature available relating to the use of mesna. In U.S. Pat. No. 4,623,742, at column 9, the sodium salt of 2-mercaptoethanesulphonic acid or the disodium salt of the corresponding disulfide metabolite is recommended as an active neuroprotective agent. However, read in context, the foregoing refers only to protection against the toxic effects of chemicals used to control cancer diseases. This is explicitly described at lines 34-48 of the same column. Moreover, at column 10, lines 10-12, the curative effect of the compounds is defined as the recidive- and metastasis-free survival of the tumor-carrying animals over 90 days. In a related patent by the same inventors, U.S. Pat. No. 4,929,607, mesna is disclosed at column 5, line 13, but appears to involve a reaction product thereof with another compound to treat cancer diseases and to produce immunosuppression in humans and animals.
A comprehensive treatise on mesna is entitled MEXAN Uroprotector, ASTA Pharma AG, Weismullerstrasse, D-6,000 Frankfort 1 FRG (December 1990). This paper describes the protective effects of mesna against chemotherapeutic drugs. At page 11, paragraph 4, the nephroprotective property of mesna is described as follows:
As witnessed by the results of animal experiments conducted by Klein and coworkers (91), Uromitexan [mesna] has also a nephroprotective effect: Mice given 600 mg/kg Holoxan.RTM. in combination with 300 mg/kg mesna did not show any kidney lesions, while mice treated with such large Holoxan.RTM. doses alone evidenced renal injuries.
At page 12 of the MEXAN publication, the author explains that both mesna and dimesna pass unchanged through the hepatic vasculature, and are neither taken up into the liver cells nor excreted in bile. In the kidneys, dimesna is said to be subject to glomerular filtration and is subsequently reabsorbed, whereupon reduction to the pharmacologically active thiol form takes place in the renal tubular epithelium.
At page 28 of the MEXAN publication, it is questioned whether mesna affects the immunosuppressive efficacy of the oxazaphosphorines. Several workers, the article relates, noticed that five out of eight patients receiving Endoxan.RTM. and mesna were found to reject the transplant. Thus, it could not be established that this finding was related to the administration of mesna. Irrespective of the foregoing, since mesna was used in conjunction with Endoxan.RTM., it would reasonably have been expected that the compound was merely exhibiting its known activity of protecting against chemotherapeutic agents.
Another description of mesna's uses appears in a monograph from Micromedex, Inc., at volume 83. In addition to reiterating mesna's use in conjunction with chemotherapeutic drugs, the article also mentions mucolytic therapy, in treating chronic bronchitis. Nevertheless, the authors conclude that mesna's efficacy was no greater than that of hypertonic saline.
In the abstracts from the VI Biennial Meeting of Free Radicals: From Basic Science to Medicine, International Society for Free Radical Research, Torino (Italy), Jun. 16-20, 1992, analogs of mesna are described wherein, instead of the sodium salt, the arginine salt of mercaptoethanesulphonic acid is employed. The arginine salt was synthesized to overcome the possible osmotic imbalance caused by a sodium overload resulting from high dose administration of mesna. At page 5.26, in the penultimate sentence, it is stated that the salification with arginine was chosen for its lack of toxicity and for its potentially positive effects of enhancing nonspecific immune response and host responses to tumors. Accordingly, it appears that argimesna (AR), like mesna, finds its principal role in counteracting the adverse effects of chemotherapeutic drugs.
However, unlike mesna, argimesna has been indicated to exhibit antioxidant properties in rabbit myocardium. At page 9.14 of said abstracts, argimesna is evaluated as a protective agent against ischemia and reperfusion damage in isolated and perfused Langendorff rabbit hearts. In the results reported, the authors state that in aerobic perfusion, AR did not produce any significant alteration of systolic and diastolic pressure. Before and during ischemia and reperfusion, AR delayed and reduced the rate of diastolic pressure on reperfusion and increased the recovery of systolic pressure. In the last sentence, the authors state that their data indicate "AR [at] 10.sup.-6 M has a protective effect against ischaemia and reperfusion damage: in our opinion, AR could work as reduced equivalent donor able to reduce the oxygen toxicity."
The same information described above is reported by the same authors in Cardio Science, 3:179-87 (1992). In other articles describing the activity of argimesna, namely, Pharmacol-Res, 25 Suppl 1:85-6 (1992) and Ann-Oncol, 3 Suppl 2:S115-8 (1992), the compound is described as being a new uroprotective agent that is safe and active in the prevention of hemorrhagic cystitis from IFO.
Previous attempts have been made to employ certain drugs containing thiol groups as antioxidants.